4354-52-3Relevant academic research and scientific papers
Synthesis, biological evaluation, and structure activity relationship (SAR) study of pyrrolidine amide derivatives as: N -acylethanolamine acid amidase (NAAA) inhibitors
Zhou, Pan,Xiang, Lei,Zhao, Dongsheng,Ren, Jie,Qiu, Yan,Li, Yuhang
supporting information, p. 252 - 262 (2019/03/02)
N-Acylethanolamine acid amidase (NAAA) is one of the key enzymes involved in the degradation of fatty acid ethanolamides (FAEs), especially for palmitoylethanolamide (PEA). Pharmacological blockage of NAAA restores PEA levels, providing therapeutic benefits in the management of inflammation and pain. In the current work, we showed the structure-activity relationship (SAR) studies for pyrrolidine amide derivatives as NAAA inhibitors. A series of aromatic replacements or substituents for the terminal phenyl group of pyrrolidine amides were examined. SAR data showed that small lipophilic 3-phenyl substituents were preferable for optimal potency. The conformationally flexible linkers increased the inhibitory potency of pyrrolidine amide derivatives but reduced their selectivity toward fatty acid amide hydrolase (FAAH). The conformationally restricted linkers did not enhance the inhibitor potency toward NAAA but improved the selectivity over FAAH. Several low micromolar potent NAAA inhibitors were developed, including 4g bearing a rigid 4-phenylcinnamoyl group. Dialysis and kinetic analysis suggested that 4g inhibited NAAA via a competitive and reversible mechanism. Furthermore, 4g showed high anti-inflammatory activities in lipopolysaccharide (LPS) induced acute lung injury (ALI) model, and this effect was blocked by pre-treatment with the PPAR-α antagonist MK886. We anticipate that 4g (E93) will enable a new agent to treat inflammation and related diseases.
3-Aminoazetidin-2-one derivatives as N-acylethanolamine acid amidase (NAAA) inhibitors suitable for systemic administration
Fiasella, Annalisa,Nuzzi, Andrea,Summa, Maria,Armirotti, Andrea,Tarozzo, Glauco,Tarzia, Giorgio,Mor, Marco,Bertozzi, Fabio,Bandiera, Tiziano,Piomelli, Daniele
, p. 1602 - 1614 (2014/07/21)
N-Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti-inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator-activated receptor α (PPAR-α). Thus, preventing PEA degradation by inhibiting NAAA may provide a novel approach for the treatment of pain and inflammatory states. Recently, 3-aminooxetan-2-one compounds were identified as a class of highly potent NAAA inhibitors. The utility of these compounds is limited, however, by their low chemical and plasma stabilities. In the present study, we synthesized and tested a series of N-(2-oxoazetidin-3-yl)amides as a novel class of NAAA inhibitors with good potency and improved physicochemical properties, suitable for systemic administration. Moreover, we elucidated the main structural features of 3-aminoazetidin-2-one derivatives that are critical for NAAA inhibition. Stability is the key: α-Amino-β-lactams were synthesized as amide derivatives, and the effect of the azetidin-2-one ring, the stereochemistry at the α-position, and the functionalization of the α-amino group were studied with regard to N-acylethanolamine acid amidase inhibitory potency and hydrolytic and plasma stability.
Nickel-butadiene catalytic system for the cross-coupling of bromoalkanoic acids with alkyl grignard reagents: A practical and versatile method for preparing fatty acids
Iwasaki, Takanori,Higashikawa, Kiyokazu,Reddy, Vutukuri P.,Ho, Willbe W. S.,Fujimoto, Yukari,Fukase, Koichi,Terao, Jun,Kuniyasu, Hitoshi,Kambe, Nobuaki
supporting information, p. 2956 - 2960 (2013/03/28)
The knights who say Ni: A practical and convenient synthetic route to fatty acids involves the Ni-catalyzed alkyl-alkyl cross-coupling of bromoalkanoic acids and alkyl Grignard reagents in the presence of 1,3-butadiene as an additive (see scheme). Copyright
